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NEUROBIOLOGICAL BASIS FOR CO-OCCURRING SUBSTANCE ABUSE AND MENTAL ILLNESS

Human Genetic Determinants of Schizophrenia and Nicotine Addiction
Sherry Leonard, Ph.D.

[Slides not available]

This study investigated the relationship between smoking, schizophrenia, and a candidate gene, the α7 nicotinic receptor (CHRNA7). The CHRNA7 receptor is decreased in expression in the hippocampus, cortex, and reticular nucleus of the thalamus in schizophrenic subjects. Promoter mutations in the CHRNA7 gene are associated with both schizophrenia and abnormal auditory-evoked potential responses (P50 deficit). A microarray comparison of gene expression in postmortem hippocampus of control and schizophrenic smokers and nonsmokers shows that smoking significantly changes the expression of 277 genes. In the schizophrenic hippocampus, smoking differentially regulated more than 70 genes. The gene groups most significantly changed by smoking were genes expressed in the NMDA postsynaptic density (NMDA-PSD) and in the immune complex. Expression for many of the genes in these two groups was differentially regulated in the schizophrenic brain. The CHRNA7 receptor, which plays a role in the regulation of the NMDA-PSD, is one of the genes differentially regulated by smoking in schizophrenia, at both the mRNA and protein levels. Generally, the expression of differentially regulated genes was abnormal in schizophrenic nonsmokers and was brought to control levels by smoking, suggesting that smoking is normalizing gene expression in the patients. This is consistent with self-medication. We have also completed a haplotype analysis of 2 kb of upstream regulatory DNA sequence in the CHRNA7 gene. The regulatory region haplotypes seem to be related to both smoking and schizophrenia. A single haplotype was strongly associated with abnormal auditory gating (P50). Two haplotypes were associated with both smoking and schizophrenia, but the association was strongest with smoking. The data suggest that the CHRNA7 genotype may regulate smoking behavior.

Animal Models of Schizophrenia and Depression: Studies on the Neurobiological Basis for Comorbidity With Drug and Alcohol Abuse
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Animal Models of Schizophrenia and Depression: Studies on the Neurobiological Basis for Comorbidity With Drug and Alcohol Abuse
R. Andrew Chambers, M.D.

Substance use disorders involving addictive drugs of differing psychoactive profiles are frequently comorbid across a broad spectrum of psychiatric disorders. Combining animal models of psychiatric disorders with preclinical addiction paradigms is a route toward understanding the fundamental brain mechanisms underlying dual-diagnosis phenomena and their heterogeneous presentations. Investigations using neurodevelopmental models of schizophrenia and adult lesion models of affective disorders suggest the unitary nature of mental illness and addiction vulnerability on the levels of major limbic neurocircuits and clinical phenomenology. Further investigations using animal models of dual diagnosis will specify how environmental and genetic determinants may conspire to alter neural networks commonly involved with psychiatric disorders and the addiction process.

Nicotine-Induced Sensitization in ADHD
Jean A. King, Ph.D.

[Slides not available]

Recent findings have shown that a disproportionate number of individuals diagnosed with attention deficit hyperactivity disorder (ADHD) are smokers. It has been hypothesized that individuals with ADHD may smoke as a means of self-medication. This study was conducted to examine the effects of nicotine administration in an animal model of ADHD. It was hypothesized that exposure to nicotine would alter behavior, monoamine levels, and neuronal activation in the ADHD animal model.

Dr. King found that nicotine differentially altered all parameters examined in the ADHD animal model, compared with controls. On behavioral indices that assessed ADHD, levels of hyperactivity decreased with chronic nicotine administration, while pain sensitivity increased in ADHD animals with nicotine administration. Meanwhile, serotonin and dopamine levels in the frontal cortex (an area implicated in ADHD) showed enhanced basal levels of both monoamines; however, nicotine differentially altered the release of these transmitters. Although nicotine induced consistent increases in dopamine levels, similar increases in serotonin levels were not observed. Finally, functional brain imaging studies support a dosage-dependent increase in neuronal activation in the brain reward circuitry, with larger increases observed in the ADHD animal model. These studies support the premise that animals exhibiting ADHD features differ in their sensitivity to nicotine.

Use Increases Risk of Adult Psychosis Only in Those With Specific COMT Genotypes
Robin M. Murray, M.D., D.Sc.

[Slides not available]

Until recently, it was suggested that individuals with psychosis used cannabis as self-medication to alleviate the distressing symptoms of schizophrenia. However, recent studies have focused on determining whether cannabis use is causal or consequential to the development of schizophrenia.

This study followed 759 individuals from age 11 (before cannabis use began), showing that individuals using cannabis at ages 15 and 18 had increased rates of developing psychotic symptoms, even with children who appeared unlikely to be predisposed by virtue of their personality and childhood. Using cannabis by age 15 was associated with increased risk for being diagnosed with schizophreniform psychosis at age 26.

Although studies investigating the interaction between cannabis use and psychosis have suggested that cannabis increases the risk of later schizophrenia, cannabis use alone does not appear to be a sufficient or necessary cause for the development of schizophrenia. The harmful effects of cannabis use appear to occur in a minority of users, suggesting that underlying factors, such as a genetic liability to psychosis, may make individuals susceptible. An obvious susceptibility gene to study in relation to cannabis use and the development of schizophrenia is catechol-O-methyltransferase (COMT), which forms part of the dopamine metabolism pathway in the prefrontal cortex. A functional polymorphism appears to moderate the effect of adolescent cannabis use on the risk for adult psychosis.

Overall, these findings support the model of schizophrenia that suggests there is a genetic background predisposing individuals to psychosis, upon which a complex constellation of factors act to trigger the development of schizophrenia. These factors include early hazards to the development of the brain; certain types of social adversity; and the abuse of such drugs as amphetamines, cocaine, and cannabis.


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